Production of 12-substituted-6, 7, 8, 9, 10, 11-hexahydrocycloocta[b]quinolines



3,318,896 Patented May 9, 1967 United States Patent Ofiice Thisapplication is a continuation-in-part of application Ser. No. 223,814,filed Sept. 14, 1962, now abandoned.

This invention relates tol2-substituted-6,7,8,9,10,1lhexahydrocycloocta[b]quinolines. Moreparticularly, the invention relates to compounds of the formula ductionof II and III.

s B is either-N or N )n R represents hydrogen or lower alkyl.

R and R,,, which may be the same or different, each represents hydrogen,lower alkyl, hydroxy-lower alkyl or phenyl-lower alkyl. In addition, thenitrogen may join with the groups represented by R and R to form a 5 to7 membered monocyclic heterocycli-c containing, if desired, an oxygen,sulful or an additional nitrogen atom. That is, the symbols R and Rtogether represent a tetramethylene, pentamethylene, hexamethylene,oxatetramethylene, oxapentamethylene, azatetramethylene,azapentamethylene, azahexamethylene, thiatetramet hylene orthiapentamethylene group. The heterocyclic group may also be besubstituted by one or two lower alkyl, halogen, lower alkoxy,hydroxy-lower alkyl or lower alkanolyoxy lower alkyl substitutes, Xrepresenting these 'substituents and hydrogen, and n representing 1 or2.

Representative substituents symbolized by R include the following: thehalogens chlorine, bromine, iodine and fluorine, of which chlorine andbromine are preferred, lower alkoxy groups such as methoxy, ethoxy,propoxy, isopropoxy, butoxy and the like. The alkyl groups included bythe symbols R, R and R are straight or branched chain saturatedaliphatic groups containing up to about 12 carbons. Lower alkyl groupssuch as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, amyl and thelike, are, however, preferred. The alkylene chains in the basicsubstituents are straight or branched chain saturated aliphatic groupsof the same character of which lower alkylene is also preferred.

The basic, nitrogen containing radical which forms part of groups II andIII above include, for example, lower alkylamino, e.g., methylamino,ethylamino, di(lower alkyl)amino, e.g., dimethylamino, diethylamino,dipropylamino, (hydroxy-lower a1kyl)amino, t.g., hydroxyethylamino,di(hydroxy-lower alkyl)amino, e.g., di-hydroxyethyl)amino, phenyl(loweralkyl)amino, e.g., benzylamino, N-(lower alkyl)-phenyl-(lower alkyl)-amino, e.g., N-methylbenzylamino, and the like. Di-lower alkylaminogroups are preferred.

Heterocyclic groups represented by the radical included for example,piperidino, (lower alkyl)piperidino, e.g., methylpiperidino, di(loweraIkyDpiperidino, e.g., dimethylpiperidino, (lower alkoxy)piperidino,e.g., methoxypiperidino, 2-, 3- or 4- piperidyl, 2-, 3- or 4-(N-loweralkylpiperidyl), e.g., 2-, 3- or 4-(N-methylpiperidyl), pyrrolidino,(lower alkyl)pyrrolidino, e.g., methylpyrrolidino, di(loweralkyl)pyrrolidino, e.g., dimethylpyrrolidino, (lower alkoxy)pyrrolidino,e.g., ethoxypyrrolidino, 2- or 3-pyrrolidyl, 2- or 3-(N-lower alkylpyrrolidyl), e.g., 2- or 3-(N-methylpyrrolidyl)morpholino, (loweralkyl)- morpholino, e.g., Z-methylmorpholino or 3-methylmorpholino,di(lower alkyl)morpholino, e.g., 2,3-dimet'hylmorpholino, (loweralkoxy)morpholino, e.g., ethoxymorpholino, thiamorpholino, (loweralkyl)-thiamorpholino, e.g., Z-methylthiamorpholino or3-methylthi-amorpholino, di(lower alkyl)thiamorpholino, e.g.,2,3-dimethylthiamorpholino, (lower alkoxy)thiamorpholino, e.g., 2-methoxythiamorpholino, piperazino, (lower alkyl)piperazino, e.g., N-methylpiperazino, Z-methylpiperazino or N -ethylpiperazino, hydroxylo'wer alkylpiperazino, e.g., hydroxy-ethylpiperazino, loweralkanoyloxy-lower alkylpiperazino, e.g., acctoxyethylpiperazino,di(lower alkyl)- piperazino, e.g., 2,3 dimethylpiperazino,hexamethyleneimino and homopiperazino. Nitrogen heterocyclic arepreferred.

A few illustrations of the complete groups II and III are thusdirnethylaminoethylamino, dimethylaminopropylamino,diethlaminoethylamino, diethylaminoethoxy, dimethylaminomethoxy,dipropylaminoethoxy, N-methyldiethylamino, N-methyldimethylamino,piperidinopropylamino, piperldinoethylamino, morpholinopropylamino,pyrrolidinopropionamido, homopiperazinomethylamino, dimethylacetamido,diethylacetamido, morpholinopropi-onamido, and the like.

The bases of Formula I form acid addition salts with the commoninorganic and organic acids. Such inorganic salts as the hydro-halides,e.g., hydrobromide, hydrochloride, hydroiodide, sulfates, nitrates,phosphates, borates, etc., and organic salts as acetate, oxalate,tartrate, malate, citrate, succinate, benzoate, ascorbate, salicylate,theophyllinate, camphorsulfonate, alkanesulfonate, e.g.,methanesulfonate, benzenesulfonate, toluenesulfonate and the like arealso within the scope of the invention. Formation of the acid additionsalt frequently provides a convenient means for readily isolating andobtaining pure product. If the free base is then desired, the salt maybe neutralized, e.g., with sodium hydroxide.

The compounds of Formula I are obtained from an R- substituted6,7,8,9,10,1 1-hexahydrocycloocta[b] quinoline- 12[5H]-one of theformula wherein R is the same as previously defined.

6 i) This starting rnaterial is derived from cyclooctanone andanthranilic acid of the formula and the residue is heated on thesteam-bath in vacuo to OOOH acid in ethanol. The salt is collected andis recrystal- R lized from a methanol-ether (1:1) mixture to give 5.5 g.

NHi (49%) of material melting between 165167 C. V v I I By following theprocedure of Example 1, but utilizing wherein R is ill: Same asPreviously defineda ring substituted12-chloro-6,7,8,9,10,1l-hexahydrocyclo- The tWO reactants are Preferablyheated together WIljh octa[b]quinoline with the radical listed in thesecond m val f Water formfid in the Tfiaction, y diitllcolumn of TableI, and substituting the amine listed in lation. the third column ofTable I for the 3-dimethylaminopro- The intermediate compounds ofFormula I wherein R ylamine in part (b), the 1 3,10 1p is a halogen areobtained from the 12-keto compound octa[b]quinoline with thesubstituents listed in the last of Formula V by reaction with aphosphorus oxyhalide column of Table I is obtained:

TABLE I Example Ring substituent Reactant Product 2.2-ethylaminoethylamine 2-methyl-12-(Z-ethylaminoethylamino). 3.B-dimethylaminooctylamine.. 3-methyl-12(S-dirnethylaminooctylamino). 4 43-[(2 hydroxyethyl)amino] propyl e2-eth0xy-12-{3-(Z-hydroxyethyl)aminopropylarnino]. 5B-benzylaminopropylamine 2-broru3-12-(3-benzylaminopropylamino). 6Z-piperidylethylamine 3-chloro-12-(2-piperidylethylamino). 7 4-chl0roZi-piperazinopropylamine 4-ehloro-1Z-(Spiperazinepropylamino). 82-chlor0 3-(2-methylm0rph0lino)propylamina...2-ch1oro-12-[3(Z-methyhnorpholino)propylammol.

such as phosphorus oxychlor'ide, phosphorus oxybromide or the like,preferably with heating. Reaction of the halogenated compound thusderived with an amine such as 3-dimethylaminopropylamine,piperidinoethylamine, 1-(Z-aminoethyl)hexamethyleneimine, preferably byheating under pressure in the presence of a catalyst such ascopper-bronze powder, yields a product of Formula I wherein the12-substituent is the group II.

Alternatively, conversion of the halogen with ammonia gives an aminogroup which will react with an aminoacyl halide such as chloroacetylchloride, bromopropionyl bromide, etc., preferably by heating in aninert organic solvent, which in turn is reacted with an amine such asammonia, dimethylamine or the like with the resultant introduction ofthe amide group III.

The compounds of this invention have a lowering effect on blood pressureand are useful in the treatment of hypertension. They may beadministered orally or parenterally in the form of tablets, capsules,elixirs, injectables or the like by incorporating the appropriate dosageof a compound of Formula ,I or a physiologically acceptable acidaddition salt thereof in a conventional vehicle according to acceptedpharmaceutical practice.

The following examples are illustrative of the invention.

EXAMPLE 1 2 chloro-(3-dimethylaminopropylamino) 6,7,89,10,11-

hexahydrocyoloocla[b]quin0line, salt with two moles of oxalic acid (a)2,12-dichl0ro-6,7,8,9,10,11-hexahydr0cycloocta[b] qainoline.Nineteengrams of 2-chloro-6,7,8,9,10,11-hexahydrocycloocta[b]quinoline-12(5H)one is added to 35 ml. ofphosphorus oxychloride and the solution refluxed for 15 minutes. Thecooled solution is poured onto 500 g. of ice and the mixture is madeammoniacal. The product is collected, dried, and recrystallized from 60ml. of hexane to give 14.5 g. (70%) of material melting between 146-148"C.

(b) 2 chloro 12 (3 dimethylaminopropylamino)- 6,7,8,9,10,I1hexahydrocycloocta[b]quinoline, dioxalate.A mixture of 6 g. of2,12-dichloro-6,7,8,9,10,11- hexahydrocyclooeta[b]quinoline, 9 g. of3-dimethylaminopropylarnine and 100 mg. of copper-bronze powder isheated in a sealed tube for hours at 180 C. The contents are extractedinto ether. The ether is removed EXAMPLE 9 2 chloro (2diethylaminoacetamido)cycl00cta[b]quilt-- oline, salt with one mole ofoxalic acid, compound with one mole of ethanol (a) 2 chloro 12 amino6,7,8,9,10,11 hexahydrocycl00cta[b]quin0line.-A solution of 10 g. of2,12-dichloro 6,7,8,9,10,11 hexahydrocycloocta[b]quinoline in 30 g. ofp-cresol is heated to 175 C. while passing in ammonia for 5 hours. Thecooled solution is poured onto chopped ice and basified with 20% sodiumhydroxide. The mixture is extracted with ether and dried over magnesiumsulfate. The ether is removed and the residue recrystallized from ml. ofbenzene to give the product.

(b) 2 chloro 12 (2 chloroacetamido) 6,7,8,9,-10,11-hexahydrocyclo0cta[b]quinoline.A mixture of 9.5 g. of2-chloro-12-amino-6,7,8,9,10,1:1-hexahydrocycloocta [b]quinoline and 5ml. of chloroacetyl chloride is heated ina sealed tube for 4 hours at C.The contents of the tube are dissolved in 500 ml. of boiling water andfiltered. The cooled filtrate is made alkaline and precipitates a tansolid. The product is collected and recrystallized from 100 ml. ofethanol to give the product.

(c) 2 chloro 12 (2 diethylaminoacetamido) 6,7,8,9,10,11hexahydr0cyel0octa[b]quinoline, oxalate with one mole of ethanol.--Asuspension of 3.9 g. of 2- chloro (2 chloroacetamido) 6,7,8,9,10,11hexahydrocycloocta[b]quinoline in ml. of toluene is reacted with 4 g. ofdiethylamine. The mixture is stirred and refluxed for 10 hours. Thecooled mixture is extracted with 5% hydrochloric acid. The acid extractis washed with ether and then is basified with an excess of concentratedammonium hydroxide. The base is taken up in ether and dried. The etheris distilled off and the residue (4.4 g.) dissolved in 10 ml. of ethanoland added to a solution of 2.9 g. of oxalic acid in 10 ml. of ethanol.The solution is diluted with one volume of anhydrous ether toprecipitate the salt. Recrystallization from isopropanol gives theproduct.

By following the procedure of Example 9(b) using either12-amino-6,7,8,9,10',11-hexahydrocycloocta[b]quinoline or thecorresponding compound with the ring substituent listed in Table II withchloroacetyl chloride or chloropropionyl chloride, as the case may be,and then substituting the amine listed in the third column of Table IIfor the diethylamine in 9(c), the6,7,8,9,10,11-hexahydrocycloocta[b]quinoline with the substituentslisted in the last column of Table II is obtained:

TABLE II Example Ring substituent Reactant Product 2-chloro Morph nlino2-chIoro-l2- (morpholinopropionamido) 2-methyl Diethylamine 2-methyl-12-(Z-diethylami no acetamido) 3-methyl 2-methylpyrrolidine3-methyl-12-(2-methylpyrrolidinoacetamido). 2-ethoxy Morpholiue2-ethoxy-12- (2-morph0linoacetarnido) Z-bromo .l Dimethylamine2-bromo-12-(2-dimethylaminopropionamido). 15 3-chloro2-hydroxyethylpiperazine3-chl0ro-12-(2-hydroxyethylpiperazinoacetamldo). 16 4-chloro Methy4-chloro-12-(Z-methylarninoacetamido).

EXAMPLE 17 4. A compound of the formula 2-chl0r0 6,7,8,9,10,11hexahydro-IZ-[Z-(hexahydro-I- azepinyl)ethylamino]cycloocta[b]quinoline,salt with two males of oxalic acid Five grams of 2,l2-dichloro-6,7,8,9,10,11-hexahydrocyclooctal[b]quinoline, 9 grams of1-(2-aminoethyl)hexamethyleneimine and :100 mg. of copper-bronze powderare reacted as described in Example 1(b) to give the dioxalate.

What is claimed is:

1. A compound selected from the group consisting of bases of the formulawherein R is a member of the group consisting of lower alkyl, loweralkoxy and halogen, R is a member of the group consisting of uN-alkylene-B, and NHC-alky1ene-B R is a member of the group consistingof hydrogen and lower alkyl, B is a member of the group consisting of Rand R is a member of the group consisting of hydrogen, lower alkyl,hydroxy-lower alkyl and phenyl-lower alkyl, R and R together are amember of the group consisting of tetramethylene, pentamethylene,hexamethylene, oxatetramethylene, oxapentamethylene, azatetramethylene,azapentamethylene, azahexamethylene, thiatetramethylene andthiapentamethylene, X is .a member of the group consisting of hydrogen,hydroxy-lower alkyl and lower alkanoyloxy-lower alkyl, and n is aninteger from 1 to 2, and physiologically acceptable acid addition saltsof said bases.

2. A compound of the formula lower alkyl NHa1kylene-N I Ower alkylhalogen 3. A compound of the formula lower alkyl NH-alkylene-N loweralkyl lower alkyl lower alkyl NH-alkylene-N lower alkyl lower alkoxy 5.A compound of the formula 1k 1 H lowera y N H- O-alkylene-N ower alkylhalogen 6 A compound of the formula 3 5 H lower alkyl NH-O-alkylene-Nlower alkyl lower alkyl 0 7. A compound of the formula H lower alkyllTIH-C-alkylene-N lower alkyl lower alkoxy References Cited by theExaminer UNITED STATES PATENTS 6,185,691 5/ 1965 'Pribyl et a1 167--653,232,945 2/1966 Sigal et a1 260288 OTHER REFERENCES Burger: MedicinalChemistry, 2nd Ed., Interscience, page 551 (1960).

A'LEX MAZEL, Primary Examiner.

7o DONALD G. DAUS, Assistant Examiner.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF BASES OF THE FORMULA